Quinoxaline derivatives useful in therapy

ABSTRACT

The invention provides compounds of formula I, ##STR1## wherein R 1  and R 2  independently represent Cl or C 1-6  alkyl; 
     R 3  represents XCO 2  R 4 , XCONHSO 2  R 5 , YNHSO 2  R 5  or XR 6  ; 
     R 4  represents H or C 1-6  alkyl (optionally substituted by aryl or heterocyclyl); 
     R 5  represents CF 3 , heterocyclyl or C 1-6  alkyl (optionally substituted by aryl or heterocyclyl); 
     R 6  represents an acidic heterocycle; 
     X represents a C 1-6  alkyl diradical (optionally subsituted by aryl or heterocyclyl); and 
     Y represents a C 2-6  alkyl diradical (optionally substituted by aryl or heterocyclyl); provided that when R 1  and R 2  each represent Cl, then R 3  does not represent CH 2  CO 2  H, CH 2  CO 2  CH 3 , CH 2  CH 2  NHSO 2  CF 3  or 5-tetrazolylmethyl; and pharmaceutically acceptable salts thereof. 
     The compounds are indicated as anxiolytics, anticonvulsants, analgesics and neuroprotectives.

This invention relates to quinoxaline derivatives useful in therapy.

L-Glutamic acid is an excitatory amino acid neurotransmitter whosephysiological role in the brain involves interaction with fourreceptors, three of which are named after the selective agonists NMDA(N-methyl-D-aspartate), AMPA(2-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid) and kainate. Thefourth receptor is termed the metabotropic receptor. In addition to abinding site for glutamic acid, the NMDA receptor possesses highaffinity binding sites for dissociative anaesthetics (e.g. ketamine),polyamines (e.g. spermine), glycine and certain metal ions (e.g. Mg²⁺,Zn²⁺). Since the NMDA receptor has an absolute requirement to bindglycine for activation to occur, glycine antagonists can act asfunctional NMDA antagonists.

In the region of a cerebral infarct, for example, anoxia causesabnormally high concentrations of glutamic acid to be released, whichleads to an over-stimulation of NMDA receptors, resulting in thedegeneration and death of neurones. Thus, NMDA receptor antagonists,which have been shown to block the neurotoxic effects of glutamic acidin vitro and in vivo, may be useful in the treatment and/or preventionof pathological conditions in which NMDA receptor activation is thoughtto be important. Examples of such conditions include neurodegenerativedisorders including senile dementia and Alzheimer's disease and thosearising from events such as stroke, transient ischaemic attack,peri-operative ischaemia and traumatic head injury to the brain orspinal cord. They may also have utility in conditions in whichperipheral nerve function has been impaired such as retinal and maculardegeneration.

Furthermore, NMDA antagonists have been shown to possess anti-convulsantand anxiolytic activity and may therefore be used to treat epilepsy andanxiety. They may also be useful in the treatment of pain.

NMDA antagonists may also attenuate the effects of alcohol withdrawalfrom physically dependent animals (K. A. Grant et al. J. Pharm. Exp.Ther. (1992), 260, 1017) and thus NMDA antagonists may be of use in thetreatment of alcohol addiction.

Various derivatives of 1,2,3,4-tetrahydroquinoline-2,4-dione have beendescribed as NMDA (glycine site) antagonists (see EP-A-0459561 andEP-A-0481676), while WO-A-91/13878 and JP-A-3220124 describe1,4-dihydroquinoxalin-2,3-diones as glutamic acid antagonists.WO-A-94/00124 describes 1,4-dihydroquinoxalin-2,3-diones (including6,7-dichloro-5-nitro-1,4-dihydroquinoxalin-2,3-dione) having highaffinity for the glycine binding site with utility for treating strokeand related disorders.

International Patent Application N° PCT/EP95/03559 (published 28 Mar.1996) discloses a number of quinoxalinsulphonamide derivatives which areindicated as anxiolytic, anticonvulsant, analgesic or neuroprotectiveagents.

According to the present invention, there is provided a compound offormula 1, ##STR2## wherein R¹ and R² independently represent Cl or C₁₋₆alkyl;

R³ represents XCO₂ R⁴, XCONHSO₂ R⁵, YNHSO₂ R⁵ or XR⁶ ;

R⁴ represents H or C₁₋₆ alkyl (optionally substituted by aryl orheterocyclyl);

R⁵ represents CF₃, heterocyclyl or C₁₋₆ alkyl (optionally substituted byaryl or heterocyclyl);

R⁶ represents an acidic heterocycle;

X represents a C₁₋₆ alkyl diradical (optionally substituted by aryl orheterocyclyl); and

Y represents a C₂₋₆ alkyl diradical (optionally substituted by aryl orheterocyclyl); provided that when R¹ and R² each represent Cl, then R³does not represent CH₂ CO₂ H, CH₂ CO₂ CH₃, CH₂ CH₂ NHSO₂ CF₃ or5-tetrazolylmethyl; and pharmaceutically acceptable salts thereof(referred to together herein as "the compounds of the inventions").

Pharmaceutically acceptable salts include salts of any acidic groupswhich may be present, for example alkali metal salts (such as sodiumsalts) of carboxylic acid groups. The dione group may also ionise andform salts with sodium, ethanolamine and diethanolamine, for example.

Alkyl groups represented by R¹, R², R⁴ and R⁵ may be straight, cyclic orbranched chain.

Alkyl diradicals represented by X and Y may be straight, cyclic orbranched chain. Examples of such groups include --CH₂ --, --CH₂ CH₂ --and --CH(CH₃)CH₂ --. Heterocyclic groups represented or comprised by R⁴,R⁵, X and Y include aromatic and non-aromatic groups containing 5 or 6ring atoms, up to 3 of which may be selected from N, O or S. Specificheterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl andthiazolyl. Optionally, such groups may be substituted by methyl orhalogen. In addition, they may be fused to a benzene ring. Therefore, R⁵may represent a methylimidazole group, for example.

"Aryl" means an aromatic hydrocarbon. Aryl groups comprised by R⁴, R⁵, Xand Y may contain 6 or 10 carbon atoms, such as phenyl or naphthyl.Optionally, they may be substituted by methyl or halogen. In addition,they may be fused to a heterocyclic ring containing 5 or 6 ring atoms,up to 3 of which may be selected from N, O or S.

Acidic heterocycles that R⁶ represents are those which, when a sample ofthem is exposed to physiological pH (7.4), more than 50% of themolecules are ionised. Examples include oxadiazolone and tetrazole. Theheterocycles may be substituted by methyl or halogen, provided that theacidity criterion set out above is still satisfied.

"Halogen" means fluoro, chloro, bromo or iodo. Preferred groups arefluoro, chloro and bromo.

In some instances the compounds of the invention may exist as tautomersand all such tautomers are included within the scope of the invention,whether separated or not. In addition compounds containing asymmetriccentres can exist as enantiomers and diastereoisomers, and the inventionincludes the separated individual isomers as well as mixtures ofisomers. In particular, rotation about the bond between the sulphonamidenitrogen atom and the 1,4-dihydro-2,3-dioxoquinoxaline ring may berestricted, and so atropisomerism may arise. Optical isomers (includingatropisomers) may be separated using conventional techniques such asfractional crystallization of diastereomeric derivatives.

Preferred groups of compounds which may be mentioned include those inwhich:

(a) R¹ represents Cl;

(b) R² represents methyl; and

(c) R³ represents CH₂ CO₂ H, CH(CH₃)CO₂ H, or (CH₂)₃ CO₂ H.

The invention further provides a process for the production of acompound of formula I, as defined above, or a pharmaceuticallyacceptable salt thereof, which comprises removing the protecting groupsfrom a compound of formula II, ##STR3## wherein R¹⁻³ are as definedabove and P¹ and P² are hydroxy protecting groups, and where desired ornecessary converting the resulting compound into a pharmaceuticallyacceptable salt or vice versa.

Protecting groups which P¹ and P² may represent include benzyl and C₁₋₆alkyl, in particular methyl. These protecting groups may be removedusing conventional deprotection methods (see `Protective Groups inOrganic Synthesis` by T W Greene and P G M Wuts, John Wiley and SonsInc, 1991). For example, when they represent methyl, they may be removedby acidic hydrolysis using dilute aqueous hydrochloric acid (e.g. 2molar). The reaction is typically carried out by heating the compound offormula II, preferably under reflux, in a mixture of dilute aqueoushydrochloric acid and a suitable organic solvent such as dioxane oracetone for, say, 2 to 48 hours until reaction is complete. The compoundof the invention can then be isolated and purified by conventionalprocedures.

Compounds of formula II, as defined above, form a further aspect of theinvention.

When protecting groups P¹ and P² are removed in the above process, if R³represents XCO₂ R⁴ and R⁴ represents C₁₋₆ alkyl (optionallysubstituted), this R⁴ group may be replaced with H by the conditions ofthe reaction. A compound of formula I in which R⁴ represents C₁₋₆ alkyl(optionally substituted) may be obtained by reaction of a correspondingcompound of formula I in which R⁴ represents H with the appropriatealcohol of formula R⁴ OH using conventional methods.

Compounds of formula II in which R³ represents XCO₂ R⁴ may be preparedby reaction of a compound of formula III, ##STR4## in which R¹, R², P¹and P² are as defined above, with a compound of formula Hal-XCO₂ R⁴,wherein Hal represents Cl, Br or I and X is as defined above. Thereaction may be carried out in the presence of a base (such as potassiumcarbonate) in a suitable solvent (such as acetone) at an elevatedtemperature (such as the reflux temperature of the solvent).

In addition, compounds of formula II in which R³ represents XCO₂ H maybe prepared by reaction of a compound of formula III, as defined above,with a compound of formula Hal-XCH₂ OH, wherein X and Hal are as definedabove, to give a compound of formula II in which R³ represents XCH₂ OH,followed by oxidation using conventional methods, such as the action ofpyridinium dichromate.

Compounds of formula II in which R³ represents YNHSO₂ R⁵ may be preparedin three stages:

(a) Alkylation of a compound of formula III, as defined above, with acompound of formula Hal-Y-(N-phthalimide), wherein Hal represents Cl, Bror I. The reaction may be carried out in the presence of a base (such aspotassium carbonate) in a suitable solvent (such as acetone) at anelevated temperature (such as the reflux temperature of the solvent).

(b) Deprotection of the alkylated compound to yield an NH₂ group. Thereaction may be carried out using hydrazine hydrate in a suitablesolvent (such as dichloromethane and methanol) at an elevatedtemperature (such as the reflux temperature of the solvent).

(c) Reaction of the amino compound with a compound of formula (R⁵ SO₂)₂O or R⁵ SO₂ Cl. The reaction may be carried out in a suitable solvent(such as dry tetrahydrofuran), at room temperature.

Compounds of formula II in which R³ represents XCONHSO₂ R⁵ or XR⁶ may beprepared from corresponding compounds of formula II in which R³represents XCO₂ R⁴ by conventional methods, as illustrated by theExamples.

Compounds of formula III can be prepared by sulphonylation of acorresponding quinoxaline of formula IV, ##STR5## in which R¹, R², P¹and P² are as defined above, using the appropriate sulphonyl chlorideCH₃ SO₂ Cl or anhydride (CH₃ SO₂)₂ O, in a suitable organic solvent,e.g. dichloromethane or tetrahydrofuran, in the presence of an acidacceptor such as pyridine or triethylamine. With some startingmaterials, if a large excess of the sulphonyl chloride or anhydride isused, then di-sulphonylation or some degree of di-sulphonylation mayoccur. In this situation, one of the CH₃ SO₂ -- substituents can beremoved by reaction of the di-sulphonylated product with aqueous sodiumhydroxide. Compounds of formula IV are known or can be prepared by knowntechniques (see for example PCT/EP95/03559).

In the synthesis of the compounds of the invention it may be necessaryor desirable to protect sensitive functional groups and then deprotectthem. Methods for such operations are known to those skilled in the artand are described in `Protective Groups in Organic Synthesis` mentionedabove.

The compounds of the invention are useful because they possesspharmacological activity in animals (including humans). In particular,the compounds are useful in the treatment or prevention ofneurodegenerative disorders (including senile dementia, Alzheimer'sdisease and those arising from events such as stroke, transientischaemic attack, peri-operative ischaemia and traumatic head injury tothe brain or spinal cord; and retinal and macular degeneration),convulsions, pain and anxiety. The treatment of stroke is of particularinterest. The compounds may also be useful in the treatment of tinnitus.

Thus, according to another aspect of the invention, there is provided ananxiolytic, anticonvulsant, analgesic or neuroprotective method oftreatment, which comprises administration of a compound of the inventionto a patient in need of such treatment. The use of the compounds of theinvention as pharmaceuticals, and the use of the compounds of theinvention in the manufacture of an anxiolytic, anticonvulsant, analgesicor neuroprotective medicament, are also provided.

The biological activity of the compounds of the invention may bedemonstrated in the tests set out below:

(a) Binding affinity for the glycine site of the NMDA receptor

This may be measured by testing a compound's ability to displace aselective glycine site radioligand from rat brain membranes as describedin Brit J Pharm (1991), 104, 74. In a variation of this method,thoroughly washed membrane protein is incubated with ³ H!-L-689,560 for90 minutes using tris-acetate buffer (pH 7.4). Displacement of theradioligand, using a range of test compound concentrations, is used toderive IC₅₀ (50% inhibitory concentration) values.

(b) Binding affinity for the AMPA receptor

This may be measured by testing a compound's ability to displace theradioligand ³ H!-AMPA from rat brain membranes. Membrane homogenate isincubated with radioligand (10 nM) in the presence or absence of testcompounds at various concentrations at 4° C. for 45 min. Free and boundradiolabel is separated by rapid filtration, and radioactivity ismeasured by liquid scintillation counting.

(c) Functional in vitro NMDA antagonism

This is demonstrated by the ability of a compound to inhibit thedepolarizations in rat cortical slices induced by NMDA, similar to themethod described in J Med Chem, (1990), 33, 789 and Brit J Pharm (1985),84, 381. In a variation of the procedure, the response to a standardconcentration of NMDA is measured in the presence of a range of testcompound concentrations, and the results obtained are used to deriveIC₅₀ (50% inhibitory concentration) values.

(d) NMDA antagonism in vivo

This can be demonstrated by the ability of a compound to inhibitNMDA-induced wild running in the mouse according to a variation of themethod described in Brit J Pharm Proceedings Supplement (1992), 107,58P. In this model, groups of mice are treated with test compounds atvarious doses prior to administration of NMDA (60 mg/kg i.v.). Thelatency of onset of wild running is recorded and the presence or absenceof this behaviour used to determine an ED₅₀. Probit analysis is used toestimate a dose at which 50% of mice fail to display wild running by 10minutes post NMDA administration.

(e) Blocking of cortical spreading depression

In vivo activity of a compound may also be demonstrated by measuring itsability to block the propagation of electrically-initiated corticalspreading depression in anaesthetised rats. Thus, male rats areanaesthetised and two glass microelectrodes are inserted into the rightparietal cortex to a depth of 0.5-1mm for recording brain activity. Inaddition, a bipolar stimulating electrode is placed on the dura in frontof the microelectrodes. The dura is then electrically stimulated at 10minute intervals, and the waves of spreading depression are detected bythe microelectrodes, amplified and displayed using a chart recorder.Test compounds are dissolved in water as their sodium salts, orhydrochloride salts (where possible) and administered by i.v. injectionat various doses to determine the minimum dose which blocks thepropagation of the spreading depression.

The compounds of the invention may be administered to a patient in needof treatment by a variety of conventional routes of administration,including oral and intravenous administration. The compounds havepotential for absorption through the gastrointestinal tract and thusadministration by slow release formulations is also possible.

In general, a therapeutically-effective oral dose is likely to rangefrom 0.1 to 100 mg/kg body weight of the subject to be treated,preferably 1 to 10 mg/kg, and an intravenous dose is likely to rangefrom 0.01-10 mg/kg of body weight of subject treated, preferably 0.1-5mg/kg. Where necessary, the compounds may also be administered byintravenous infusion, at a dose which is likely to range from 0.01-1mg/kg/hr. In practice the physician will determine the actual dosagewhich will be most suitable for an individual patient and it will varywith age, weight and response of the particular patient. The abovedosages are exemplary of the average case but there can, of course, beindividual instances where higher or lower dosage ranges are merited,and such are within the scope of the invention.

Although the compounds of the invention can be administered alone, theywill generally be administered in admixture with a pharmaceuticalcarrier selected with regard to the intended route of administration andstandard pharmaceutical practice. For example, oral administration maybe in the form of tablets containing such excipients as starch orlactose, in capsules either alone or in admixture with excipients, or inthe form of elixirs or suspensions containing flavouring or colouringagents. The compounds may be injected parenterally, for exampleintravenously, intramuscularly or subcutaneously. For parenteraladministration they are best used in the form of a sterile aqueoussolution of an appropriate salt of the compound and the solution maycontain other substances such as salts to make it isotonic with blood.

Thus, there is further provided a pharmaceutical formulation comprisinga compound of the invention, in admixture with a pharmaceuticallyacceptable adjuvant, diluent or carrier.

The compounds of the invention may have the advantage that they are morepotent, more soluble, more selective for example being potentantagonists of the NMDA (glycine site) receptor but with little or noaffinity for the AMPA receptor!, less toxic or possess other moredesirable properties than the compounds of the prior art.

The invention is illustrated by the following Examples, in which thefollowing abbreviations are used:

    ______________________________________    APCI        atmospheric pressure chemical ionisation    DMF         dimethyl formamide    DMSO        dimethylsulphoxide    ______________________________________

Melting points were determined using a Buchi apparatus in glasscapillary tubes and are uncorrected. Spectroscopic data were recorded onPerkin-Elmer 983 (Infra Red), Fisons Trio 1000 (Mass Spectrometer,thermospray using ammonium acetate in aqueous methanol as carrier), andBruker AC300 and Varian Unity 300 NMR instruments (both 300 MHz), andwere consistent with the assigned structures. Column chromatography wasaccomplished on Kieselgel 60, (230-400 mesh) from E. Merck, Darmstadt.Kieselgel 60 F₂₅₄ plates from E. Merck were used for thin layerchromatography (TLC), and compounds were visualised with UV light orchloroplatinic acid/potassium iodide solution. In cases where compoundsanalysed as hydrates, the presence of water was evident in the enhancedpeak due to water in the proton NMR spectra. The purity of compounds wascarefully assessed using analytical TLC and proton NMR (300 MHz), andthe latter technique was used to calculate the amount of solvent insolvated samples. In multistep sequences, the purity and structure ofintermediates were verified spectroscopically by proton NMR. Proton NMRshifts are quoted in parts per million downfield from tetramethylsilane.

EXAMPLE 1N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)-N-(2-(N'-methanesulphonyl)-aminoethyl)methanesulphonamide##STR6##

(a) A mixture of 6,7-dichloro-1,4-dihydro-5-nitroquinoxalin-2,3-dione(Example 1 of WO-A-94/00124, 84 g, 0.34 mol), thionyl chloride (840 ml)and dimethylformamide (0.5 ml) was heated at reflux for 3 hours, cooledand concentrated under reduced pressure. Ethyl acetate (300 ml) wasadded and removed under reduced pressure, followed by petroleum ether(bp 100°-120° C.). The solid residue was recrystallised from petroleumether (bp 100°-120° C.) to give 2,3,6,7-tetrachloro-5-nitro-quinoxaline(78 g, 73%) as a light yellow solid.

¹ H-NMR (300 MHz, CDCl₃): δ=8.6 (1H, s).

(b) Tin (II) chloride dihydrate (346.3 g, 1.54 mol) was added to asolution of 2,3,6,7-tetrachloro-5-nitro-quinoxaline (96.2 g, 0.31 mol)in ethyl acetate (1.8 l). The mixture was heated under reflux for 4hours, cooled and poured cautiously into an excess of aqueous saturatedsodium bicarbonate. The mixture was filtered through "Celite", (TradeMark), washing well with ethyl acetate. The filter cake was maceratedwith more ethyl acetate and the solid material filtered off. Thecombined ethyl acetate solutions were dried (MgSO₄) and concentratedunder reduced pressure to give 5-amino-2,3,6,7-tetrachloroquinoxaline(73.4 g, 84%) as a yellow solid.

¹ H NMR (300 MHz, CDCl₃): δ=5.45 (2H, broad s), 7.47 (1H, s). m/z(thermospray) 385 (MH⁺).

(c) A solution of sodium methoxide (25% solution in methanol, 274 ml,1.28 mol) was added to a suspension of5-amino-2,3,6,7-tetrachloroquinoxaline (72.4 g, 0.256 mol) in drymethanol (1 l) and the resulting mixture was heated at reflux for 30minutes. The mixture was cooled, concentrated under reduced pressure,and the residue partitioned between water and ethyl acetate (total of 8l). The organic solution was dried (MgSO₄) and concentrated underreduced pressure. The crude product was purified by trituration withmethanol, followed by dissolution in dichloromethane (2 l) andfiltration. The filtrate was concentrated under reduced pressure to give5-amino-6,7-dichloro-2,3-dimethoxy-quinoxaline as a yellow solid (55.0g, 79%).

¹ H NMR (300 MHz, CDCl₃): δ=4.13 (3H, s), 4.14 (3H, s), 5.07 (2H, broads), 7.26 (1H, s). m/z (thermospray) 274 (MH⁺).

(d) A mixture of 5-amino-6,7-dichloro-2,3-dimethoxyquinoxaline (10.0 g,36.5 mmol), methanesulphonic anhydride (31.8 g, 183 mmol) and pyridine(14.8 ml, 183 mmol) in dry dichloromethane (150 ml) was stirred at 20°C. for 16 hours. The solvent was removed under reduced pressure and theresidue dissolved in a mixture of water (5 ml) and tetrahydrofuran (50ml). After being stirred for 10 minutes, the solution was partitionedbetween ethyl acetate and 2M hydrochloric acid. The combined organicsolutions were washed with saturated aqueous sodium bicarbonate, dried(MgSO₄), and concentrated under reduced pressure. Purification of theresidue by flash chromatography (gradient elution withhexane/dichloromethane) gave 6,7-dichloro-5-di(methanesulphonyl)amino-2,3-dimethoxyquinoxaline as an off-white solid (12.3 g, 78%), mp240°-244° C.

¹ H NMR (300 MHz, CDCl₃): δ=3.62 (6H, s), 4.16 (3H, s), 4.18 (3H, s),8.02 (1H, s). m/z (thermospray) 430, 432 (MH⁺).

(e) Aqueous sodium hydroxide (1M, 145 ml, 145 mmol) was added to asuspension of6,7-dichloro-5-di(methanesulphonyl)amino-2,3-dimethoxy-quinoxaline(12.28 g, 28.6 mmol) and the mixture was stirred at room temperature for16 hours. The resulting orange solution was treated with 2M hydrochloricacid (to pH 3) and the solid which precipitated was filtered off, washedwith water and ether, and dried under reduced pressure at 80° C. to giveN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide (8.46g, 84%) as a white solid, mp 225°-227° C.

¹ H NMR (300 MHz, CDCl₃): δ=3.42 (3H, s), 4.15 (3H, s), 4.20 (3H, s),7.15 (1H, broad s), 8.02 (1H, s). m/z (thermospray) 352 (MH⁺).

(f) N-(2-bromoethyl)phthalimide (1.73 g, 6.81 mmol) was added to arefluxing mixture ofN-(6,7-dichloro-2,3-dimethoxy-quinoxalin-5-yl)-methanesulphonamide (2.00g, 5.68 mmol) and potassium carbonate (1.88 g, 13.63 mmol) in acetone(100 ml) under nitrogen. After 48 hours, furtherN-(2-bromoethyl)phthalimide (1.73 g, 6.81 mmol) was added and refluxingcontinued for 18 hours. After cooling the mixture was concentrated underreduced pressure and the residue dissolved in dichloromethane. Theresulting solution was washed twice with 1N sodium hydroxide solution,water and brine and then dried (MgSO₄) and concentrated under reducedpressure. The residue was purified by flash chromatography (eluting withhexane:ethyl acetate) to affordN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-phthalimidoethyl)methanesulphonamideas a pale yellow solid (2.55 g, 85%).

¹ H NMR (300 MHz, CDCl₃) δ=3.25 (3H, s), 3.64 (2H, t, J 8Hz), 3.90-4.02(2H, m), 4.12 (3H, s), 4.17 (3H, s), 7.65-7.80 (3H, m), 7.82-7.92 (2H,m). m/z (thermospray) 525 (MH⁺).

(g) Hydrazine hydrate (696 μl, 716 mg, 14.3 mmol) was added dropwise toa solution ofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-phthalimidoethyl)methanesulphonamide(3.76 g, 7.15 mmol) in a mixture of dichloromethane (71 ml) and methanol(5 ml) at room temperature under nitrogen. The mixture was heated atreflux for 4 days and then further methanol (20 ml) was added. After afurther 2 days the mixture was allowed to cool and was concentratedunder reduced pressure. The residue was dissolved in ethyl acetate andthis was extracted 3 times with 10% aqueous citric acid. The combinedacid extracts were adjusted to pH 9 with solid potassium carbonate andextracted 3 times with dichloromethane. The combined dichloromethaneextracts were dried (MgSO₄) and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting with95:5 dichloromethane:methanol to giveN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-aminoethyl)methanesulphonamide(1.96 g, 69%) as a pale yellow solid.

¹ H NMR (300 MHz, CDCl₃) δ=2.70-2.88 (2H, m), 3.11 (3H, s), 3.79 (2H, t,J 8Hz), 4.17 (3H, s), 4.20 (3H, s), 7.95 (1 H, s). m/z (thermospray) 395(MH⁺).

(h) A mixture ofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-aminoethyl)-methanesulphonamide(250 mg, 0.632 mmol), pyridine (61 μl, 60 mg, 0.759 mmol) andmethanesulphonic anhydride (132 mg, 0.759 mmol) in dry tetrahydrofuran(6.5 ml)was stirred at room temperature under nitrogen for 2 days.Further pyridine (61 μl, 60 mg, 0.759 mmol) and methanesulphonicanhydride (132 mg, 0.759 mmol) were added and stirring continued for afurther 2 days. This was repeated again and after another 2 dayspyridine (122 μl, 120 mg, 1.518 mmol) and methanesulphonic anhydride(264 mg, 1.518 mmol) were added. After another 2 days (8 days in total)water was added and the mixture was partitioned between water and ethylacetate. The organic layer was washed with 2M hydrochloric acid, water,saturated sodium bicarbonate solution, water and brine and then dried(MgSO₄) and concentrated under reduced pressure to giveN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-(N'-methanesulphonyl)-aminoethyl)methanesulphonamide(116 mg, 39%).

¹ H NMR (300 MHz, CDCl₃) δ=2.90 (3H, s), 3.16 (1H, m), 3.21 (3H, s),3.37 (1H, m), 4.00 (2H, m), 4.18 (3H, s), 4.21 (3H, s), 5.60 (1H, s),7.99 (1H, s). m/z (thermospray) 473 (MH⁺).

(i) A mixture ofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-(N'-methanesulphonyl)aminoethyl)methanesulphonamide (112 mg, 2.37 mmol), 2M hydrochloric acid(1.2 ml) and 1,4-dioxan (2.5 ml) was heated at reflux for 18 hours.After cooling the mixture was concentrated under reduced pressure andthe residue triturated with ether and the resulting solid collected byfiltration and dried under reduced pressure at 60° C. The title compound(70 mg, 66%) was obtained as a foam.

¹ H NMR (300 MHz, DMSO-d₆) δ=2.84 (3H, s), 3.16 (2H, m), 3.23 (3H, s),3.79 (2H, m), 7.02 (1H, s), 7.40 (1H, s), 10.55 (1H, s), 12.10 (1H, s).m/z (thermospray) 462 (MNH₄ ⁺).

EXAMPLE 2N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)-N-(2-(N'-4-(1H-1-methylimidazolyl)sulphonyl)aminoethyl)methanesulphonamide ##STR7##

(a) A mixture ofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-aminoethyl)-methanesulphonamide(Example 1 step (g), 200 mg, 0.506 mmol), pyridine (49 μl, 48 mg, 0.607mmol) and 1-methylimidazole-4-sulphonyl chloride (110 mg, 0.607 mmol) indry dichloromethane (5 ml) was stirred at room temperature undernitrogen for 24 hours. Further pyridine (49 μl, 48 mg, 0.607 mmol) and1-methylimidazole-4-sulphonyl chloride (110 mg, 0.607 mmol) were addedand stirring continued for a further 3 days. The mixture was washed withwater, 2M hydrochloric acid, water, saturated sodium bicarbonatesolution, water and brine and then dried (MgSO₄) and concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with 95:5 dichloromethane:methanol to giveN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-(N'-4-(1H-1-methylimidazolyl)sulphonyl) aminoethyl)methanesulphonamide (203 mg,74%).

¹ H NMR (300 MHz, CDCl₃) δ=3.05 (1H, m), 3.22 (3H, s), 3.28 (1H, m),3.66 (3H, s), 4.00 (2H, m), 4.18 (3H, s), 4.24 (3H, s), 6.00 (1H, s),7.21 (1H, s), 7.26 (1H, s, obscured), 7.96 (1H, s). m/z (thermospray)539 (MH⁺).

(b) The title compound was prepared fromN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-(N'-4-(1-methylimidazolyl)sulphonyl)-aminoethyl)methanesulphonamide (198 mg, 0.387 mmol) by themethod of Example 1 step (i) and was obtained as a foam (119 mg, 63%).

Analysis %: Found, C, 31.14; H, 3.51; N, 14.12. C₁₅ H₁₆ Cl₂ N₆ O₆ S₂.HCl. 2H₂ O requires: C, 30.86; H, 3.63; N, 14.39.

EXAMPLE 3N-(Carboxymethyl)-N-(1,4-dihydro-7-chloro-6-methyl-2,3-dioxoquinoxalin-5-yl)methanesulphonamide##STR8##

(a) A mixture of 1,2-diamino-4-chloro-5-methylbenzene hydrochloride JChem Soc, 117, 784 (1920)! (1.90 g, 9.84 mmol), oxalic acid (1.24 g,13.8 mmol) and 4M hydrochloric acid (49 ml) was heated at reflux for 4.5hours. After cooling the solid precipitate was collected by filtration,washed well with water and dried under reduced pressure at 80° C. toafford 1,4-dihydro-6-chloro-7-methylquinoxalin-2,3-dione (1.68 g, 81%)as a dark grey solid, mp>330° C.

Analysis %: Found; C, 51.58; H, 2.98; N, 13.27. C₉ H₇ ClN₂ O₂ requiresC, 51.32; H, 3.35; N, 13.30.

(b) 1,4-dihydro-6-chloro-7-methylquinoxalin-2,3-dione (1.26 g, 5.98mmol) was added in portions over 3 minutes to vigorously stirred conc.nitric acid at room temperature. The resulting heterogeneous mixture wasthen warmed to 40° C. and stirred for 12 hours. After cooling the yellowmixture was poured into ice-water (100 ml) and this was stirred for 30minutes. The resulting yellow precipitate was collected by filtration,washed with water and dried by suction to afford a mixture of1,4-dihydro-6-chloro-7-methyl-5-nitroquinoxalin-2,3-dione and1,4-dihydro-7-chloro-6-methyl-5-nitroquinoxalin-2,3-dione (1:2 ratio,1.35 g, 88%) as a yellow solid.

¹ H NMR (300 MHz, CDCl₃) δ=2.23 (2H, s), 2.35 (1H, s), 7.19 (0.3H, s),7.30 (0.7H, s), 11.9-12.25 (2H, broad m).

(c) A mixture of1,4-dihydro6-chloro-7-methyl-5-nitroquinoxalin-2,3-dione and1,4-dihydro-7-chloro-6-methyl-5-nitroquinoxalin-2,3-dione (1.35 g, 5.73mmol), thionyl chloride (12.5 ml, 20.4 g, 0.172 mmol) anddimethylformamide (44 μl, 42 mg, 0.573 mmol) was heated at reflux for41/4 hours producing a clear yellow solution. After cooling the mixturewas cautiously added to vigorously stirred ice-water (300 ml). Theresulting precipitate was collected by filtration, washed with water anddried by suction to give a mixture of2,3,7-trichloro-6-methyl-5-nitroquinoxal and2,3,6-trichloro-7-methyl-5-nitro-quinoxaline (2:1 ratio, 1.45 g, 87%) asa straw-coloured powder. This mixture could be separated with difficultyfor characterisation purposes by flash chromatography (gradient elutionwith hexaneldichloromethane) to give first2,3,7-trichloro-6-methyl-5-nitroquinoxaline as a white solid, mp164°-165° C.

Analysis %: Found, C,36.76; H,1.37; N,14.43. C₉ H₄ Cl₃ N₃ O₂ requires:C, 36.96; H, 1.38; N, 14.37.

The second eluted isomer, 2,3,6-trichloro-7-methyl-5-nitro-quinoxalinewas obtained as a straw-coloured solid, mp 121°-122° C.

Analysis %: Found, C, 39.78; H, 2.02; N, 13.23. C₉ H₄ Cl₃ N₃ O₂. 0.22hexane requires: C, 39.80; H, 2.29; N, 13.49.

(d) A mixture of 2,3,7-trichloro-6-methyl-5-nitroquinoxaline and2,3,6-trichloro-7-methyl-5-nitro-quinoxaline (250 mg, 0.855 mmol) andstannous chloride dihydrate (1.35 g, 5.98 mmol) in ethyl acetate (8.5ml) was heated at reflux for 3 hours under nitrogen. After cooling themixture was diluted with ethyl acetate (50 ml) and washed with 10%aqueous sodium carbonate solution (2×25 ml) and brine (25 ml) and thendried (MgSO₄), filtered and concentrated under reduced pressure toafford a mixture of 5-amino-2,3,7-trichloro-6-methylquinoxaline and5-amino-2,3,6-trichloro-7-methylquinoxaline (217 mg, 97%) as an orangesolid.

¹ H NMR (300 MHz, CDCl₃) δ=2.41 (2H, s), 2.55 (1H, s), 5.03 (1.3H, broads), 5.08 (0.7H, broad s), 7.23 (0.3H, s), 7.44 (0.7H, s). m/z(thermospray) 262 (MH⁺).

(e) A 25% solution of sodium methoxide in methanol (433 μl, 1.89 mmol)was added dropwise to a solution of5-amino-2,3,7-trichloro-6-methylquinoxaline and5-amino-2,3,6-trichloro-7-methylquinoxaline (200 mg, 0.788 mmol) in drytetrahydrofuran (7.9 ml) at 0° C. under nitrogen. The mixture wasstirred for 31/4 hours and then diluted with ethyl acetate (30 ml) andwashed with water (2×10 ml) and brine (10 ml) and then dried (MgSO₄)filtered and concentrated under reduced pressure. The solid residue waspurified by flash chromatography on silica gel, eluting with ahexane/ethyl acetate gradient giving5-amino-6-chloro-2,3-dimethoxy-7-methylquinoxaline as an off-whitesolid, mp 169°-170° C.

Analysis %: Found, C, 53.80; H, 5.16; N, 16.18. C₁₁ H₁₂ ClN₃ O₂. 0.15hexane requires: C, 53.61; H, 5.33; N, 15.76. The second elutedcompound, 5-amino-7-chloro-2,3-dimethoxy-6-methylquinoxaline, wasobtained as an orange solid, mp 181°-182° C.

Analysis %: Found, C, 52.55; H, 4.72; N, 16.61. C₁₁ H₁₂ ClN₃ O₂. 0.05hexane requires: C, 52.61; H, 4.96; N, 16.29.

(f) Pyridine (80 μl, 78 mg, 0.985 mmol) and methanesulphonic anhydride(172 mg, 0.985 mmol) were added to a solution of5-amino-7-chloro-2,3-dimethoxy-6-methylquinoxaline (50 mg, 0.197 mmol)in dry tetrahydrofuran (1.6 ml) at room temperature under nitrogen.After stirring for 17 hours water (0.3 ml) was added and stirringcontinued for 1 hour. The mixture was diluted with ethyl acetate (15 ml)and washed with 2M hydrochloric acid (5 ml), water(5 ml), saturatedsodium bicarbonate solution (5 ml) and brine (5 ml) and then dried(MgSO₄), filtered and concentrated under reduced pressure to affordN-(7-chloro-2,3-dimethoxy-6-methylquinoxalin-5-yl)methanesulphonamide(66 mg, 100%) as a white solid mp 228°-229° C.

Analysis %: Found, C, 43.51; H, 3.98; N, 12.60. C₁₂ H₁₄ ClN₃ O₄ Srequires: C, 43.44; H; 4.25; N, 12.60.

(g) A mixture ofN-(7-chloro-2,3-dimethoxy-6-methylquinoxalin-5-yl)methanesulphonamide(694 mg, 2.09 mmol), potassium carbonate (347 mg, 2.51 mmol) and acetone(21 ml) was heated at reflux for 10 minutes and was then allowed to coolto room temperature. Methyl bromoacetate (396 μl, 640 mg, 4.19 mmol) wasadded and the mixture was heated at reflux for 18 hours. The mixture wasallowed to cool to room temperature and was concentrated under reducedpressure. The residue was dissolved in dichloromethane and washed twicewith water and then brine and then dried (MgSO₄) and concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with dichloromethane to giveN-(7-chloro-2,3-dimethoxy-6-methylquinoxalin-5-yl)-N-(methoxycarbonylmethyl)methanesulphonamideas a white solid (407 mg, 48%).

¹ H NMR (300 MHz, CDCl₃) δ=2.73 (3H, s), 3.18 (3H, s), 3.72 (3H, s),4.13 (3H, s), 4.19 (3H, s), 4.20 (1H, d, J 19Hz), 4.79 (1H, d, J 19Hz),7.85 (1H, s). m/z (thermospray) 404 (MH⁺).

(h) The title compound was prepared fromN-(7chloro-2,3-dimethoxy-6-methylquinoxalin-5-yl)-N-(methoxycarbonylmethyl)methanesulphonamide(404 mg, 1.00 mmol) by the method of Example 1 step (i) but trituratingwith water in place of ether and was obtained as a white solid (283 mg,78%) mp>300° C.

Analysis %: Found, C, 40.18; H, 3.47; N, 11.25. C₁₂ H₁₂ ClN₃ O₆ Srequires: C, 39.84; H, 3.34; N, 11.65.

EXAMPLE 4N-(1,4-Dihydro-7-chloro-6-methyl-2,3-dioxoquinoxalin-5-yl)-N-(2-(N'-methanesulphonyl)-aminoethyl)methanesulphonamide##STR9##

(a)N-(7-Cholro-6-methyl-2,3-dimethoxyquinoxalin-5-yl)-N-(2phthalimidoethyl)-methanesulphonamidewas prepared fromN-(7-chloro-6-methyl-2,3-dimethoxy-quinoxalin-5-yl)-methanesulphonamide(Example 3 step (f), 2.00 g, 5.68 mmol) by the method of Example 1 step(f) and was obtained as a solid (4.57 g, 47%).

¹ H NMR (300 MHz, CDCl₃)δ=2.63 (3H, s), 3.12 (3H, s), 3.90 (2H, m), 4.08(3H, s), 4.14 (3H, s), 4.25 (2H, t, J 4 Hz), 7.69 (4H, m), 7.79 (1H, s).m/z (thermospray) 505.6 (MH⁺).

(b)N-(7-chloro-6-methyl-2,3-dimethoxyquinoxalin-5-yl)-N-(2-aminoethyl)-methanesulphonamidewas prepared fromN-(7-chloro-6-methyl-2,3-dimethoxyquinoxalin-5-yl)-N-(2-phthalimidoethyl)methanesulphonamide(4.57 g, 9.05 mmol) by the method of Example 1 step (g) and was obtainedas a pale yellow solid (2.89 g, 85%).

¹ H NMR (300 MHz, CDCl₃)δ=2.62 (3H, s), 2.81 (2H, m), 3.18 (3H, s), 3.89(2H, t, J 4 Hz), 4.16 (6H, s), 7.88 (1H, s). m/z (thermospray) 375.4(MH⁺).

(c) Trifluromethanesulphonic anhydride (99 μl, 166 mg, 0.587 mmol) wasadded to a solution ofN-(7chloro-6-methyl-2,3-dimethoxyquinoxalin-5-yl)-N-(2-aminoethyl)methanesulphonamide(200 mg, 0.534 mmol) and triethylamine (53 μl, 35 mg, 0.587 mmol) in drydichloromethane (5 ml) at -78° C. under nitrogen. The mixture wasstirred for 1 hour at -78° C. and was then allowed to warm to roomtemperature and was stirred for 18 hours. The reaction mixture waswashed with water, saturated sodium bicarbonate solution, water andbrine and then dried (MgSO₄), filtered and concentrated under reducedpressure to yield a pale yellow solid (149 mg). The solid was suspendedin 1,4-dioxan (2 ml) and 1M sodium hydroxide (1.2 ml) was addeddropwise. The resulting solution was stirred for 1 hour and was thenneutralised to pH 7 with 2M hydrochloric acid and concentrated underreduced pressure. The residue was partitioned between dichloromethaneand water and the organic layer was washed with water and brine anddried (MgSO₄), filtered and concentrated under reduced pressure to yieldN-(7-chloro-6-methyl-2,3-dimethoxyquinoxalin-5-yl)-N-(2-(N'-trifluoromethanesulphonyl)aminoethyl)-methanesulphonamideas a white solid (100 mg, 37%).

¹ H NMR (300 MHz, CDCl₃) δ=2.60 (3H, s), 3.19 (3H, m), 3.29 (1H, s),3.50 (1H, m), 3.91 (1H, m), 4.08 (1H, m), 4.18 (6H, s), 7.92 (1H, s).m/z (thermospray) 507.5 (MH⁺).

(d) The title compound was prepared fromN-(7-chloro-6-methyl-2,3-dimethoxyquinoxalin-5-yl)-N-(2-(N'-trifluoromethanesulphonyl)aminoethyl)methanesulphonamide(100 mg, 0.197 mmol) by the method of Example 1 step (i) and wasobtained as an off-white foam (62 mg, 66%).

¹ H NMR (300 MHz, CDCl₃) δ=2.30 (3H, s), 3.15 (2H, m, obscured), 3.23(3H, s), 3.71 (2H, t, J 7 Hz), 7.22 (1H, s), 9.38 (1H, s), 10.58 (1H,s), 11.96 (1H, s). m/z (thermospray) 495.7 (MNH₄ ⁺).

EXAMPLE 5 (+)- and(-)-N-(Carboxymethyl)-N-(1,4-dihydro-6-chloro-7-methyl-2,3-dioxoquinoxalin-5-yl)methanesulphonamide##STR10##

(a) Pyridine (80 μl, 78 mg, 0.985 mmol) and methanesulphonic anhydride(172 mg, 0.985 mmol) were added to a solution of5-amino-6-chloro-2,3-dimethoxy-7-methylquinoxaline (Example 3 step (e),50 mg, 0.197 mmol) in dry tetrahydrofuran (1.6 ml) at room temperatureunder nitrogen. After stirring for 24 hours further pyridine (32 μl, 31mg, 0.394 mmol) and methanesulphonic anhydride (69 mg, 0.394 mmol) wereadded. After a further 16 hours water (0.6 ml) was added and stirringcontinued for 1 hour. The mixture was diluted with ethyl acetate (15 ml)and washed with 2M hydrochloric acid (5 ml), water (5 ml), saturatedsodium bicarbonate solution (5 ml) and brine (5 ml) and then dried(MgSO₄), filtered and concentrated under reduced pressure. The solidresidue was purified by flash chromatography on silica gel eluting with3:1 hexane:ethyl acetate to giveN-(6-chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)methanesulphonamide(55 mg, 84%) as a white solid mp 198° C.

¹ H NMR (300 MHz, CDCl₃) δ=2.58, (3H, s), 3.38 (3H, s), 4.15 (3H, s),4.18 (3H, s), 7.00 (1H, broad s), 7.60 (1H, s). m/z (thermospray) 332(MH⁺). v_(max) (KBr) 3230, 2950, 1480 and 1150 cm⁻¹.

(b)N-(6-Chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)-N-(methoxycarbonylmethyl)methanesulphonamidewas prepared fromN-(6-chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)methanesulphonamide(641 mg, 1.93 mmol) by the method of Example 3 step (g) and was obtainedafter an additional trituration with ether as a solid (364 mg, 47%).

¹ H NMR (300 MHz, CDCl₃) δ=2.58 (3H, s), 3.40 (3H, s), 3.70 (3H, s),4.13 (3H, s), 4.20 (3H, s), 4.41 (1H, d, J 19 Hz), 4.47 (1H, d, J 19Hz), 7.69 (1H, s). m/z (thermospray) 404 (MH⁺).

(c)(±)-N-(Carboxymethyl)-N-(1,4-dihydro-6-chloro-7-methyl-2,3-dioxo-quinoxalin-5-yl)methanesulphonamidewas prepared fromN-(6-chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)-N-(methoxycarbonylmethyl)methanesulphonamide(360 mg, 0.892 mmol) by the method of Example 1 step (i) but trituratingwith water in place of ether and was obtained as a white solid (300 mg,93%) mp>300° C.

Analysis %: Found, C, 37.28; H, 3.80; N, 10.83. C₁₂ H₁₂ ClN₃ O₆ S. 1.5H₂O requires: C, 37.07; H, 3.89; N. 10.81.

(d) Quinine trihydrate (1.38 g, 3.66 mmol) was added to a boilingsuspension ofN-(carboxymethyl)-N-(1,4-dihydro-6-chloro-7-methyl-2,3-dioxoquinoxalin-5-yl)methanesulphonamide(1.39 g, 3.66 mmol) in methanol (110 ml) and the mixture was boiled for30 minutes. The resulting precipitate was collected by filtration fromthe hot mixture, washed well with methanol and dried under reducedpressure at 80° C. to give a white solid (1.05 g) which wasrecrystallised from methanol and dried under reduced pressure at 60° C.to leave a single diastereoisomeric quinine salt (698 mg, 28%), mp279°-280° C.

Analysis %: Found, C, 55.51; H, 5.28; N, 10.05. C₃₂ H₃₆ ClN₅ O₈ S. 0.4H₂O requires: C, 55.43; H, 5.35; N, 10.10. α!_(D) ²⁵ =-142° (c=0.1,Ethanol).

Concentrated hydrochloric acid (2 ml) was added to a stirred suspensionof the quinine salt (mp 279°-280° C.) (572 mg, 0.773 mmol) in water (40ml) at room temperature and the mixture stirred for 1 hour. The solidwas collected by filtration, washed with water and dried under reducedpressure at 80° C. to give the first title compound (240 mg, 86%) as awhite crystalline solid, mp 304°-305° C. (decomposes).

Analysis %: Found, C, 38.87; H, 3.52; N, 10.97. C₁₂ H₁₂ ClN₃ O₆ S. 0.5H₂O requires: C, 38.87; H, 3.53; N, 11.33. α!₅₄₆ ²⁵ =+3.00° (c=0.1,Ethanol).

The filtrate from the salt formation was concentrated to a volume of80ml and then stirred at room temperature for 2 hours. A crystallinesolid formed and was collected by filtration, washed with methanol anddried under reduced pressure at 80° C. to give a white solid (611 mg)which was recrystallised from methanol and dried under reduced pressureat 60° C. to give a second diastereoisomeric quinine salt (295 mg, 12%),mp 230°-232° C.

Analysis %: Found, C, 55.40; H, 5.39; N, 10.11. C₃₂ H₃₆ ClN₅ O₈ S. 0.4H₂O requires: C, 55.43; H, 5.35; N, 10.10. α!_(D) ²⁵ =-117° (c=0.1,Ethanol).

Concentrated hydrochloric acid (2 ml) was added to a stirred suspensionof the second quinine salt (mp 230°-232° C.) (616 mg, 0.832 mmol) inwater (40 ml) at room temperature and the mixture stirred for 30minutes. The solid was collected by filtration, washed with water anddried under reduced pressure at 80° C. to give the second title compound(276 mg, 92%) as a white crystalline solid, mp 302°-304° C.(decomposes).

Analysis %: Found, C, 38.48; H, 3.58; N, 11.27. C₁₂ H₁₂ ClN₃ O₆ S.0.75H₂ O requires: C, 38.41; H, 3.63; N, 11.20. α!₅₄₆ ²⁵ =-3.00° (c=0.1,Ethanol).

EXAMPLE 6N-(1,4-Dihydro-6-chloro-7-methyl-2,3-dioxoquinoxalin-5-yl)-N-(2-(N'-methanesulphonyl)aminoethyl)methanesulphonamide##STR11##

(a)N-(6-Chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)-N-(2-phthalimidoethyl)methanesulphonamidewas prepared fromN-(6-chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)-methanesulphonamide(Example 5 step (a), 3.41 g, 10.3 mmol) by the method of Example 1 step(f) but also adding sodium iodide (1.54 g, 10.3 mmol) to the reactionmixture and was obtained as a solid (4.12 g, 79%).

¹ H NMR (300 MHz, CDCl₃) δ=2.52 (3H, s), 3.23 (3H, s), 3.98 (2H, m),4.10 (3H, s) 4.12 (3H, s), 4.20 (2H, m), 7.71 (5H, m). m/z (thermospray)504.7 (MH⁺).

(b)N-(6-Chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)-N-(2-aminoethyl)-methanesulphonamidewas prepared fromN-(6-chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)-N-(2-phthalimidoethyl)methanesulphonamide(4.12 g, 8.16 mmol) by the method of Example 1 step (g) and was obtainedas white solid (2.29 g, 69%).

¹ H NMR (300 MHz, CDCl₃) δ=2.58 (3H, s), 2.80 (2H, m), 3.20 (3H, s),3.86 (2H, t, J 4 Hz), 4.17 (3H, s), 4.19 (3H, s), 7.70 (1H, s). m/z(thermospray) 375.1 (MH⁺).

(c)N-(6-Chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)-N-(2-(N'-trifluoromethanesulphonyl)aminoethyl)methanesulphonamidewas prepared fromN-(6-chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)-N-(2-aminoethyl)methanesulphonamide(200 mg, 0.534 mmol) by the method of Example 4 step (c) and wasobtained as a pale yellow solid (265 mg, 98%).

¹ H NMR (300 MHz, CDCl₃) δ=2.58 (3H, s), 3.19 (3H, m), 3.23 (1H, m),3.58 (1H, m), 3.92 (1H, m), 4.12 (1H, m), 4.19 (3H, s), 4.22 (3H, s),7.78 (1H, s). m/z (thermospray) 506.6 (MH⁺).

(d) The title compound was prepared fromN-(6-chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)-N-(2-(N'-trifluoromethanesulphonyl)aminoethyl)-methanesulphonamide(264 mg, 0.521 mmol) by the method of Example 1 step (i) and wasobtained as an off-white foam 169 mg, 68%).

Analysis %: Found, C, 31.68; H, 3.68; N, 10.76. C₁₃ H₁₄ ClF₃ N₄ O ₆ S.1.5H₂ O. 0.2Et₂ O requires: C, 31.83; H, 3.68; N, 10.76.

EXAMPLE 7N-(Carboxymethyl)-N-(1,4dihydro-6,7-dimethyl-2,3-dioxoquinoxalin-5-yl)methanesulphonamide##STR12##

(a) 1,4-Dihydro-6,7-dimethylquinoxalin-2,3-dione (J. Liebigs Ann. Chem.,1982, 754-761, 10.0 g, 52.6 mmol) was added in portions over 10 minutesto concentrated nitric acid (density, 1.42 gcm⁻³, 100 ml) at 0° C. After5 minutes, the cooling bath was removed and the mixture was stirred at20° C. for 7 hours, using cooling when necessary to maintain thistemperature. The solution was poured into iced water, and the resultingsolid filtered off and dried under reduced pressure at 75° C. to give1,4-dihydro-6,7-dimethyl-5-nitroquinoxalin-2,3-dione (7.44 g, 60%) as apale yellow solid, mp 280°-290° C. (dec.) (fromdimethylformamide/water).

¹ H NMR (300 MHz, DMSO-d₆): δ=2.08 (3H, s), 2.25 (3H, s), 7.06 (1H, s),11.70 (1H, broad s), 12.06 (1H, broad s). v_(max). (KBr) 3185, 1703,1533, 1400, 1355 cm⁻¹. m/z (thermospray) 253 (MNH₄ ⁺).

(b) A mixture of 1,4-dihydro-6,7-dimethyl-5-nitroquinoxalin-2,3-dione(7.44 g, 31.6 mmol), thionyl chloride (69.2 ml, 0.949 mol) anddimethylformamide (0.25 ml, 3.16 mmol) was heated at reflux for 3 hours,cooled, and added gradually to a vigorously stirred mixture of ice andwater (1.2 l) over 15 minutes. The resulting precipitate was filteredoff and dried under reduced pressure at 80° C. to afford2,3-dichloro-6,7-dimethyl-5-nitroquinoxaline (8.34 g, 97%), as a paleorange solid, mp 133°-134° C.

¹ H NMR (300 MHz, DMSO-d₆): δ=2.38 (3H, s), 2.54 (3H, s), 8.12 (1H, s).v_(max). (KBr) 1537, 1388, 1377, 1269, 1163 cm⁻¹. m/z (thermospray) 289(MNH₄ ⁺).

(c) A mixture of 2,3-dichloro-6,7-dimethyl-5-nitroquinoxaline, 8.33 g,30.6 mmol) and stannous chloride dihydrate (34.54 g, 153 mmol) in ethylacetate (300 ml) was heated at reflux for 11 hours. A further portion ofstannous chloride dihydrate (13.82 g, 61.2 mmol) was added and themixture was heated for 2 hours, cooled and diluted with ethyl acetate(500 ml). The mixture was added to saturated aqueous sodium bicarbonate(200 ml) and filtered, washing the filter cake well with ethyl acetate.The organic layer was separated, washed with saturated aqueous sodiumbicarbonate (3×100 ml), dried (MgSO₄) and concentrated under reducedpressure. The residue was purified by flash chromatography (gradientelution with methanol/dichloromethane) to afford5-amino-2,3-dichloro-6,7-dimethylquinoxaline (6.15 g, 83%), as an orangesolid, mp 178°-180° C.

¹ H NMR (300 MHz, DMSO-d₆): δ=2.38 (3H, s), 2.54 (3H, s), 8.12 (1H, s).v_(max) (KBr) 3475, 1613, 1267, 1178 cm⁻¹. m/z (thermospray) 242 (MNH₄⁺).

(d) Sodium methoxide (25% solution in methanol, 13.9 ml, 61 mmol) wasadded over 12 minutes to a stirred solution of5-amino-2,3-dichloro-6,7-dimethylquinoxaline (6.15 g, 25.4 mmol) in drytetrahydrofuran (250 ml) under nitrogen at 0° C. The mixture was stirredat 0° C. for 20 minutes, and at room temperature for 72 hours. Themixture was diluted with ethyl acetate (750 ml), washed with water(2×250 ml) and brine (250 ml), dried (MgSO₄), and concentrated underreduced pressure. The residue was purified by flash chromatography(gradient elution with hexane/dichloromethane) to give5-amino-2,3-dimethoxy-6,7-dimethylquinoxaline (4.55 g, 77%) as a whitesolid, mp 166°-167° C.

¹ H NMR (300 MHz, CDCl₃): δ=2.32 (3H, s), 2.35 (3H, s), 4.14 (3H, s),4.15 (3H, s), 5.06 (2H, broad s), 7.06 (1H, s). v^(max). (KBr) 3540,2950, 1600, 1535, 1395, 1335, 1240 cm⁻¹. m/z (thermospray) 234 (MH⁺).

(e) A mixture of 5-amino-2,3-dimethoxy-6,7-dimethylquinoxaline (50 mg,0.214 mmol), methanesulphonic anhydride (187 mg, 1.07 mmol) and pyridine(87 ml, 1.07 mmol) in dry tetrahydrofuran (1 ml) was stirred at 20° C.for 2.7 hours. Water (0.3 ml) was added, and the mixture was stirred for40 minutes. The mixture was partitioned between ethyl acetate (15 ml)and 2M hydrochloric acid (5 ml). The organic solution was washed withsaturated aqueous sodium bicarbonate (5 ml), dried (MgSO₄), andconcentrated under reduced pressure to giveN-(2,3-dimethoxy-6,7-dimethylquinoxalin-5-yl)methanesulphonamide (63 mg,94%) as a white solid, mp 219° C.

¹ H NMR (300 MHz, CDCl₃): δ=2.46 (3H, s), 2.55 (3H, s), 2.87 (3H, s),4.16 (6H, s), 7.00 (1H, broad s), 7.57 (1H, s). v_(max). (KBr) 3545,1480, 1160 cm⁻¹. m/z (thermospray) 312 (MH⁺).

Analysis %: Found C, 50.02; H, 5.48; N, 13.35; S, 10.51. C₁₃ H₁₇ N₃ SO₄requires C, 50.15; H, 5.50; N, 13.50; S, 10.30.

(f)N-(2,3-dimethoxy-6,7-dimethylquinoxalin-5-yl)-N-(methoxycarbonyl-methyl)methanesulphonamidewas prepared fromN-(2,3-dimethoxy-6,7-dimethylquinoxalin-5-yl)methanesulphonamide (1.00g, 3.2 mmol) by the method of Example 3 step (g) and was obtained as apale yellow solid (633 mg, 51%).

¹ H NMR (300 MHz, CDCl₃) δ=2.45 (3H, s), 2.65 (3H, s), 3.15 (3H, s),3.72 (3H, s), 4.13 (3H, s), 4.15 (3H, s), 4.44 (1H, d, J 18 Hz), 4.80(1H, d, J 18 Hz), 7.64 (1H, s). m/z (thermospray) 384 (MH⁺).

(g) The title compound was prepared fromN-(2,3-dimethoxy-6,7-dimethylquinoxalin-5-yl)-N-(methoxycarbonylmethyl)methanesulphonamide(360 mg, 0.892 mmol) by the method of Example 1 step (i) and wasobtained as a white solid (504 mg, 94%) mp>300° C.

Analysis %: Found, C, 45.31; H, 4.37; N, 12.13. C₁₃ H₁₅ N₃ O₆ S. 0.25H₂O requires: C, 45.15; H, 4.52; N, 12.15.

EXAMPLE 8N-(Carboxymethyl)-N-(1,4-dihydro-6-chloro-7-ethyl-2,3-dioxoquinoxalin-5-yl)methanesulphonamide##STR13##

(a) A mixture of 5-chloro-4-ethyl-2-nitroaniline (supplied by theSigma-Aldrich Library of Rare Chemicals, 2.62 g, 13.1 mmol), tin (II)chloride dihydrate (14.7 g, 65.3 mmol) and ethyl acetate (130 ml) washeated under reflux for 22h. The mixture was cooled and partitionedbetween 1M aqueous sodium hydroxide (500 ml) and ethyl acetate (500 ml).The aqueous layer was extracted with ethyl acetate (250 ml), and thecombined organic solutions were washed with saturated aqueous sodiumchloride (100 ml), dried (MgSO₄) and concentrated under reduced pressureto give 1,2-diamino4-chloro-5-ethylbenzene (2.70 g, >100%) as a whitesolid which was used directly without further purification.

¹ H NMR (300 MHz, CDCl₃) δ=1.19 (3H, t, J 7 Hz), 2.63 (2H, q, J 7 Hz),3.30 (4H, broad s), 6.57 (1H, s), 6.70 (1H, s).

(b) A mixture of 1,2-diamino4-chloro-5-ethylbenzene (2.70 g, ca 13mmol), oxalic acid (1.65 g, 18.3 mmol) and 4M hydrochloric acid (66 ml)was heated at reflux for 4.6 h, cooled, and the grey solid collected byfiltration and washed with water. The solid was dried under reducedpressure at 50° C. to afford1,4-dihydro-6-chloro-7-ethylquinoxalin-2,3-dione (2.34 g, 80%), mp>315°C.

Analysis %: Found, C, 53.60; H, 3.87; N, 12.40. C₁₀ H₉ ClN₂ O₂ requires:C, 53.47; H, 4.04; N, 12.47.

¹ H NMR (300 MHz, DMSO-d₆) δ=1.17 (3H, t, J 7 Hz), 2.66 (2H, q, J 7 Hz),7.05 (1H, s), 7.14 (1H, s), 11.78 (1H, broad s), 11.82 (1H, broad s).

(c) 1,4-Dihydro-6-chloro-7-ethylquinoxalin-2,3-dione (2.34 g, 10.4 mmol)was added in small portions over 10 minutes to vigorously stirredconcentrated nitric acid (20 ml) at room temperature. The mixture wasthen heated at 40° C. for 12h, cooled, and poured into ice water. Theyellow solid which formed was filtered off, washed with water, and driedto give 1,4-dihydro-6-chloro-7-ethyl-5-nitroquinoxalin-2,3-dione and1,4-dihydro-7-chloro-6-ethyl-5-nitroquinoxalin-2,3-dione (2.55 g, 91%),as a mixture (1.7:1 ratio).

¹ H NMR (300 MHz, DMSO-d₆) δ=1.09-1.19 (3H, m), 2.56 (1.3H, q, J 7 Hz),2.71 (0.7H, q, J 7 Hz), 7.19 (0.4H, s), 7.29 (0.6H, s), 11.95-12.15 (2H,broad m). m/z (thermospray) 287 (MNH₄ ⁺).

(d) A mixture of1,4-dihydro-6-chloro-7-ethyl-5-nitroquinoxalin-2,3-dione and1,4-dihydro-7-chloro-6-ethyl-5-nitroquinoxalin-2,3-dione (2.75 g, 11mmol), thionyl chloride (28.6 ml, 0.305 mol) and N,N-dimethylformamide(85 μl, 1.0 mmol) was heated under nitrogen at reflux for 24h. Thesolution was cooled and cautiously added dropwise to stirred ice-water(600 ml). After 1 h, the beige solid was filtered off, washed with waterand dried under reduced pressure to afford a mixture of2,3,7-trichloro-6-ethyl-5-nitroquinoxaline and2,3,6-trichloro-7-ethyl-5-nitroquinoxaline (2.26 g, 67%). Purificationof the mixture by flash chromatography (eluting withhexane:dichloromethane 3:1) permitted isolation of small quantities ofthe two isomers for characterisation purposes. The first eluted isomer,2,3,6-trichloro-7-ethyl-5-nitroquinoxaline had mp 106°-109° C.

Analysis %: Found C, 39.21; H, 1.99; N, 13.71. C₁₀ H₆ Cl₃ N₃ O₂ requiresC, 39.18; H, 1.97; N, 13.71.

¹ H NMR (300 MHz, CDCl₃) δ=1.41 (3H, t, J 7 Hz), 3.06 (2H, q, J 7 Hz),8.02 (1H, s). m/z (thermospray) 323 (MH⁺). The second eluted isomer,2,3,7-trichloro-6-ethyl-5-nitroquinoxaline had mp 88°-92° C.

Analysis %: Found C, 39.06; H, 1.87; N, 13.85. C₁₀ H₆ Cl₃ N₃ O₂ requiresC, 39.18; H, 1.97; N, 13.71.

¹ H NMR (300 MHz, CDCl₃) δ=1.35 (3H, t, J 8 Hz), 2.98 (2H, q, J 8 Hz),8.19 (1H, s). m/z (thermospray) 323 (MH⁺).

(e) A mixture of 2,3,7-trichloro-6-ethyl-5-nitroquinoxaline and2,3,6-trichloro-7-ethyl-5-nitroquinoxaline (200 mg, 0.652 mmol), tin(II) chloride dihydrate (1.03 g, 4.57 mmol) and ethyl acetate (6.5 ml)was heated under reflux for 4h, cooled and diluted with ethyl acetate.The solution was washed with 10% aqueous sodium carbonate (25 ml). Theaqueous layer was extracted with ethyl acetate (2×25 ml), and thecombined organic solutions were washed with 10% aqueous sodium carbonate(2×25 ml), saturated aqueous sodium chloride (25 ml), dried (MgSO₄) andconcentrated under reduced pressure to give5-amino-2,3,7-trichloro-6-ethylquinoxaline and5-amino-2,3,6-trichloro-7-ethylquinoxaline as an orange solid (174 mg,91%), ratio 1:1.

¹ H NMR (300 MHz, CDCl₃) δ=1.25 (1.5H, t, J 8 Hz), 1.37 (1.5H, t, J 8Hz), 2.84-2.98 (2H, m), 5.05 (1 H, broad s), 5.28 (1H, broad s), 7.22(0.5H, s), 7.43 (0.5H, s).

(f) A mixture of 5-amino-2,3,7-trichloro6-ethylquinoxaline and5-amino-2,3,6-trichloro-7-ethylquinoxaline (169 mg, 0.611 mmol) inanhydrous tetrahydrofuran (6 ml) was treated with a 25% solution ofsodium methoxide in methanol (0.84 ml, 1.47 mmol) at 0° C. withstirring. After 3.5 hours, the solution was diluted with ethyl acetate,washed with water (2×10 ml), saturated aqueous sodium chloride (10 ml),dried (MgSO₄) and concentrated under reduced pressure. Purification byflash chromatography (eluting with hexane/ethyl acetate 19:1) gave twoproducts. The first eluted compound,5-amino-6-chloro-7-ethyl-2,3-dimethoxyquinoxaline (42 mg, 26%), wasobtained as a white solid.

¹ H NMR (300 MHz, CDCl₃) δ=1.32 (3H, t, J 8 Hz), 2.87 (2H, q, J 7 Hz),4.18 (6H, s), 4.90 (2H, br s), 7.08 (1H, s). The second eluted compound,5-amino-7-chloro-6-ethyl-2,3-dimethoxy-quinoxaline (57 mg, 35%), wasobtained as a pale green solid.

¹ H NMR (300 MHz, CDCl₃) δ=1.14 (3H, t, J 7 Hz), 2.84 (2H, q, J 7 Hz),4.12 (3H, s), 4.14 (3H, s), 4.70 (2H, broad s), 7.22 (1 H, s).

(g) Methanesulphonic anhydride (671 mg, 3.85 mmol) was added to astirred solution of 5-amino-6-chloro-7-ethyl-2,3-dimethoxyquinoxaline(207 mg, 0.77 mmol) and anhydrous pyridine (305 mg, 3.85 mmol) inanhydrous tetrahydrofuran (7.7 ml) at room temperature. After 72h, water(3 ml) was added and the mixture was stirred for a further 60 minutes.The mixture was diluted with ethyl acetate and washed with 2Mhydrochloric acid (50 ml), water (50 ml), saturated aqueous sodiumbicarbonate (50 ml) and saturated aqueous sodium chloride (50 ml). Theorganic phase was dried (MgSO₄) and concentrated under reduced pressureto giveN-(6-chloro-7-ethyl-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide(206 mg, 77%).

¹ H NMR (300 MHz, CDCl₃) δ=1.37 (3H, t, J 8 Hz), 2.89-3.00 (2H, m), 3.39(3H, s), 4.16 (3H, s), 4.19 (3H, s), 7.01 (1H, s), 7.60 (1H, s). m/z(thermospray) 346 (MH⁺).

(h)N-(6-Chloro-2,3-dimethoxy-7-ethylquinoxalin-5-yl)-N-(methoxycarbonyl-methyl)methanesulphonamidewas prepared fromN-(6-chloro-7-ethyl-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide(500 mg, 1.45 mmol) by the method of Example 3 step (g) but purifyingthe crude product by triturating with hexane instead of by flashchromatography.

The product was obtained as a white solid (455 mg, 75%), mp160.5°-162.5° C.

Analysis %: Found C, 45.95; H, 4.78; N, 9.92. C₁₆ H₂₀ N₃ O₆ SCl requiresC, 45.99; H, 4.82; N, 10.06.

(i) The title compound was prepared fromN-(6-chloro-7-ethyl-2,3-dimethoxyquinoxalin-5-yl)-N-(methoxycarbonylmethyl)methanesulphonamide(300 mg, 0.719 mmol) by the method of Example 1 step (i) but afterconcentration under reduced pressure the crude product was dissolved in1N sodium hydroxide, washed twice with dichloromethane and acidifiedwith 2M hydrochloric acid. The resulting precipitate was collected byfiltration and dried under reduced pressure to afford the title compoundas a pale yellow solid (211 mg, 78%), mp 273°-275° C.

Analysis %: Found C, 40.27; H, 3.81; N, 10.74. C₁₃ H₁₄ N₃ O₆ SCl. 0.75H₂O requires C, 40.11; H, 4.01; N, 10.79.

EXAMPLE 9N-(Carboxymethyl)-N-(1,4-dihydro-7-chloro-6-ethyl-2,3-dioxoquinoxalin-5-yl)methanesulphonamide##STR14##

(a) 5-Amino-7-chloro-6-ethyl-2,3-dimethoxyquinoxaline (Example 8 step(f)) was converted toN-(7-chloro-6-ethyl-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide bythe method of Example 8 step (g) and was obtained in 47% yield.

¹ H NMR (300 MHz, CDCl₃) δ=1.25 (3H, t, J 8 Hz), 3.00 (3H, s), 3.28 (2H,q, J 7 Hz), 4.17 (3H, s), 4.27 (3H, s), 6.87 (1H, s), 7.83 (1H, s). m/z(thermospray) 346 (MH⁺).

(b)N-(7-Chloro6-ethyl-2,3-dimethoxyquinoxalin-5-yl)-N-(methoxycarbonylmethyl)-methanesulphonamidewas prepared fromN-(7-chloro-6-ethyl-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide(500 mg, 1.45 mmol) by the method of Example 8 step (h) and was obtainedas a white solid (497 mg, 82%), mp 165°-168° C.

Analysis %: Found C, 45.89; H, 4.81; N, 9.86. C₁₆ H₂₀ N₃ O₆ SCl requiresC, 45.99; H, 4.82; N, 10.06.

(c) The title compound was prepared fromN-(7-chloro-6-ethyl-2,3-dimethoxy-quinoxalin-5-yl)-N-(methoxycarbonylmethyl)methanesulphonamide(300 mg, 0.719 mmol) by the method of Example 8 step (i) and wasobtained as a white solid (231 mg, 86%), mp>300° C. (decomposes).

Analysis %: Found C, 41.26; H, 3.67; N, 10.93. C₁₃ H₁₄ N₃ O₆ SClrequires C, 41.55; H, 3.76; N, 11.18.

EXAMPLE 10N-(1,4-Dihydro-6-chloro-7-ethyl-2,3-dioxoquinoxalin-5-yl)-N-(methoxycarbonylmethyl)methanesulphonamide##STR15##

A mixture ofN-(carboxymethyl)-N-(1,4-dihydro-6,7-dimethyl-2,3-dioxoquinoxalin-5-yl)methanesulphonamide(Example 7, 200 mg, 0.587 mmol) and methanol (10 ml) saturated withhydrogen chloride gas was heated at reflux for 18 hours and then allowedto cool to room temperature. The mixture was concentrated under reducedpressure and the residue triturated with methanol and dried underreduced pressure to give the title compound (122 mg, 59%) as a whitesolid, mp 296.5°-299° C.

Analysis %: Found C, 47.02; H, 4.77; N, 11.76. C₁₄ H₁₇ N₃ O₆ S requiresC, 47.32; H, 4.82; N, 11.82.

EXAMPLE 11N-(1,4-Dihydro-6-chloro-7-ethyl-2,3-dioxoquinoxalin-5-yl)-N-(ethoxycarbonylmethyl)methanesulphonamide##STR16## The title compound was prepared by the method of Example 10substituting ethanol for methanol and was obtained as a white solid(87%), mp>300° C.

Analysis %: Found C, 48.41; H, 5.14; N, 11.35. C₁₅ H₁₉ N₃ O₆ S. 0.1H₂ Orequires C, 48.54; H, 5.21; N, 11.32.

EXAMPLE 12N-(1,4-Dihydro-6-chloro-7-ethyl-2,3-dioxoquinoxalin-5-yl)-N-(n-proyloxycarbonylmethyl)methanesulphonamide##STR17## The title compound was prepared by the method of Example 10substituting n-propanol for methanol and was obtained as a white solid(86%), mp 240°-242° C.

Analysis %: Found C, 49.93; H, 5.49; N. 10.87. C₁₆ H₂₁ N₃ O₆ S. 0.1H₂ Orequires C, 50.12; H, 5.52; N, 10.96.

EXAMPLE 13(RS),(RS)-N-(1-Carboxyethyl)-N-(1,4-dihydro-6-chloro-7-methyl-2,3-dioxoquinoxalin-5-yl)methanesulphonamide##STR18##

(a)(RS),(RS)-N-(6-chloro-7-methyl-2,3-dimethoxyquinoxalin-5-yl)-N-(1-methoxycarbonylethyl)methanesulphonamidewas prepared fromN-(6-chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)methanesulphonamide(Example 5, step (a)) by the method of Example 3 step (g), substitutingmethyl 2-bromopropionate for methyl bromoacetate, and obtained as amixture of diastereoisomers (as determined by NMR) (48%). mp 142°-145°C.

¹ H NMR (300 MHz, CDCl₃): δ=1.12 (2H,d, major, J 9 Hz), 1.27 (1H,d,minor, J 9 Hz), 2.58 (2H, s, major), 2.59 (1H, s. minor), 3.32 (2H, s,major), 3.36 (1H, s, minor), 3.63 (1H, s, minor), 3.82 (2H, s, major),4.15 (2H, s, major), 4.17 (s, 1H, minor), 4.20 (2H, s, major), 4.22 (1H, s, minor), 5.00 (1/3H, q, minor, J 9 Hz), 5.09 (2/3H, q, major J 9Hz), 7.70 (2/3H, s, major), 7.72 (1/3H, s, minor). m/z (thermospray) 418(MH⁺).

(b) The title compound was prepared from the compound of step (a) (100mg, 0.24 mmol) by the method of Example 1 step (i), but refluxing for 72hours. The product was obtained as white solid (62 mg, 69%).

¹ H NMR (300 MHz, DMSO-d₆): δ=1.81 (3H,d,J 8 Hz), 2.35 (3H,s), 3.13(3H,s), 4.47 (1H,q,J 8 Hz), 7.14 (1H,s), 11.88, broad s), 12.12(1H,broad s).

EXAMPLE 14N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)-N-(1,3,4-oxadiazolon-5-yl)methylmethanesulphonamide ##STR19##

(a) A mixture ofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(methoxycarbonylmethyl)-methanesulphonamide(Example 71, WO 96/09295, 1.0 g, 2.357 mmol), 1M sodium hydroxide (12ml) and 1,4-dioxan (25 ml) was stirred at room temperature for 15minutes. The resulting solution was acidified to ca. pH5 with 2Mhydrochloric acid and concentrated under reduced pressure. The residuewas suspended in water (10 ml), collected by filtration and dried underreduced pressure at 80° C. to giveN-(carboxymethyl)-N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide(876 mg, 91 %) as a white solid, mp 203°-206° C.

Analysis %: Found, C, 36.64; H, 3.12; N, 9.79. C₁₃ H₁₃ Cl₂ N₃ O₆ S. 0.67H₂ O requires C, 36.99; H, 3.42; N, 9.95.

(b) A mixture ofN-(carboxymethyl)-N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide(500 mg, 1.219 mmol) and N,N'-carbonyldiimidazole (296 mg, 1.828 mmol)in dry tetrahydrofuran (15 ml) was heated at reflux for 1 hour, cooledand concentrated under reduced pressure. The residue was partitionedbetween dichloromethane (20 ml) and water (10 ml). The organic solutionwas dried (MgSO₄) and concentrated under reduced pressure. The residuewas dissolved in dry tetrahydrofuran and hydrazine hydrate (122 mg,2.438 mmol) added. After stirring at room temperature for 3 hours, thesolvent was removed under reduced pressure and the residue partitionedbetween dichloromethane (20 ml) and saturated brine (10 ml). The aqueouslayer was extracted with dichloromethane (20 ml) and the combinedorganic solutions were dried (MgSO₄) and concentrated under reducedpressure. Purification by flash chromatography on silica gel, elutingwith dichloromethane:methanol 98:2, gaveN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(hydrazinocarbonylmethyl)methanesulphonamide(150 mg, 29%) as a white solid.

¹ H NMR (300 MHz, DMSO-d₆): δ=3.40 (3H,s), 4.07 (3H,s), 4.14 (3H,s),4.15 (1H,d,J11 Hz), 4.62 (1H,d, J11 Hz), 8.06 (1H,s), 9.08 (1H, broads). m/z (thermospray) 424 (MH⁺).

(c) A mixture of the product of step (b) (150 mg, 0.354 mmol) andN,N'-carbonyidiimidazole (69 mg, 0.425 mmol) in 1,4-dioxan (4 ml) washeated at reflux for 3 hours, cooled to room temperature andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel, eluting with dichloromethane:methanol98:2, to giveN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(1,3,4-oxadiazolon-5-yl)methanesulphonamide(89 mg, 56%) as a white solid.

Analysis %: Found, C, 37.19; H, 3.14; N, 14.52. C₁₄ H₁₃ N₅ O₆ Cl₂ S.0.19CH₂ Cl₂.0.05 Dioxan requires: C,36.71; H, 2.95; N, 14.88. m/z(thermospray) 450 (MH⁺).

(d) The title compound was prepared from the compound of step (c) (74mg, 0.164 mmol) by the method of Example 1 step (i) and was obtained asa brown solid (48 mg, 69%).

¹ H NMR (300 MHz, DMSO-d₆): δ=3.24 (3H,s), 4.18 (1H,d,J 18 Hz), 4.72(1H, d,J 18 Hz), 7.40 (1H,s), 11.30 (1H broad s),12.24 (1H, broad s).

EXAMPLE 15N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)-N-(1,2,4-oxadiazolon-3-yl)methylmethanesulphonamide##STR20##

(a) A mixture ofN-(6,7-dichloro-2,3-dimethoxyqunoxalin-5-yl)-N-(cyanomethyl)methanesulphonamide(Example 89(a), WO 96/09295, 1.54 g, 3.937 mmol), hydroxylaminehydrochloride (328 mg, 4.724 mmol) and sodium carbonate (250 mg, 2.362mmol) in absolute ethanol (10 ml) was heated at reflux for 5 hours. Theresulting suspension was filtered hot and the filtrate allowed to coolto room temperature. The precipitated crystals were collected byfiltration and dried under reduced pressure at 60° C. to giveN-(2-amino-2-hydroxyiminoethyl)-N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide(852 mg, 51%).

¹ H NMR (300 MHz, CDCl₃): δ=3.22 (3H,s), 4.15 (3H,s), 4.17 (3H,s), 4.29(1H,d,J 12 Hz) 4.38 (1H,d, J12 Hz). 5.26 (2H, broad s), 7.96 (1H,s). m/z(thermospray) 424 (MH⁺).

(b) The product of step (a) (852 g, 2.008 mmol) was dissolved in drypyridine (12 ml) and cooled to 0° C. Ethyl chloroformate (479 mg, 4.418mmol) was added over 5 minutes. The mixture was stirred at roomtemperature for 16 hours and poured into ice-cold water (40 ml). Theresulting precipitate was collected by filtration and dried underreduced pressure at 60° C. to giveN-(2-amino-2-ethoxycarbonyloxyiminoethyl)-N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide(757 mg, 76%).

¹ H NMR (300 MHz, CDCl₃) δ:1.30 (3H,t,J 8 Hz), 3.21 (3H,s), 4.14 (3H,s),4.16 (3H,s), 4.20 (2H,q,J 8 Hz), 4.36 (1H,d,J 16 Hz), 4.50 (1H,d,J 16Hz), 5.71 (2H, broad s), 7.97 (1 H,s). m/z (thermospray) 496 (MH⁺).

(c) A mixture of the product of step (b) (387 mg, 0.78 mmol) and 1Msodium hydroxide (0.78 ml, 0.78 mmol) in tetrahydrofuran (4 ml) andwater (4 ml) was stirred at room temperature for 2 hours, heated at 50°C. for 3 hours and then cooled to room temperature. The mixture waspartitioned between ethyl acetate (20 ml) and 2M hydrochloric acid (20ml). The aqueous layer was extracted with ethyl acetate (20 ml) and thecombined organic solutions were dried (Na₂ SO₄) and concentrated underreduced pressure. Purification by flash chromatography on silica gel,eluting with hexane:ethyl acetate 3:1 gaveN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(1,2,4-oxadiazolon-3-yl)methanesulphonamideas a white solid (137 mg, 39%).

¹ H NMR (400 MHz, CDCl₃): δ=3.27 (3H,s), 4.18 (3H,s), 4.22 (3H,s), 4.62(1H,d,J 14 Hz), 4.80 (1H,d, J14 Hz), 8.03 (1H,s). m/z (APCI) 450 (MH⁺).

(d) The title compound was prepared from the product of step (c) (122mg, 0.271 mmol) by the method of Example 1 step (i) and was obtained asan off-white solid (38 mg, 33%) mp>300° C.

Analysis %: Found, C, 32.30; H, 2.77; N, 15.13. C₁₂ H₉ N₅ O₆ Cl₂ S. 1.6H₂ O requires: C, 31.96; H, 2.73; N, 15.53.

EXAMPLE 16(RS).(RS)-N-(α-carboxybenzyl)-N-(1,4-dihydro-6-chloro-7-methyl-2,3-dioxoquinoxalin-5-yl)methanesulphonamide##STR21##

(a)(RS),(RS)-N-(6-chloro-7-methyl-2,3-dimethoxyquinoxalin-5-yl-N-(α-methoxycarbonylbenzyl)methanesulphonamidewas prepared fromN-(6-chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)methanesulphonamide(Example 5 step (a)) by the method of Example 3 step (g), substitutingmethyl-α-bromophenylacetate for methyl bromoacetate, and obtained as amixture of diastereoisomers (as determined by NMR) (87%). mp 214°-217°C.

Analysis %: Found, C, 52.35; H, 4.61; N, 8.55. C₂₁ H₂₂ N₃ O₆ ClSrequires: C, 52.56; H, 4.62; N, 8.76.

(b) The title compound was prepared from the product of step (a) (150mg, 0.313 mmol) by the method of Example 1 step (i), but refluxing for120 hours. The product was obtained as an off-white solid (89 mg, 65%).mp 279° C. (decomposes).

Analysis %: Found, C, 46.24; H, 4.25; N, 8.39. C₁₈ H₁₆ N₃ O₆ S. 2H₂ O.0.17 Et₂ O requires: C, 46.12; H, 4.50; N, 8.64. m/z (thermospray) 455(MNH₄ ⁺).

EXAMPLE 17N-(4-Carboxybutyl-N-(1,4-dihydro-6-chloro-7-methyl-2,3-dioxouinoxalin-5-yl)methanesulphonamide##STR22##

(a)N-(6-Chloro-7-methyl-2,3-dimethoxyquinoxalin-5-yl)-N-(4-methoxycarbonylbutyl)methanesulphonamidewas prepared fromN-(6-chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)methanesulphonamide(Example 5, step (a)) (1.00 g, 3.01 mmol) by the method of Example 3,step (g) substituting methyl-5-bromovalerate (1.16 g, 6.03 mmol) formethyl bromoacetate, and obtained as a white solid (0.77 g, 57%).

¹ H NMR (300 MHz, CDCl₃): δ=1.57-1.70(4H, m), 2.24 (2H, t, J 6 Hz), 2.48(3H, s), 3.19 (3H, s), 3.61 (3H, s), 3.80 (2H, t, J6 Hz), 4.17 (6H,s),7.71 (1H,s). m/z (thermospray) 446 (MH⁺).

(b) The title compound was prepared from the product of step (a) (0.82g, 1.85 mmol) by the method of Example 1, step (i) and was obtained as abeige solid (0.68 g, 91%).

Analysis %: Found, C, 44.32; H, 4.51; N, 10.18. C₁₅ H₁₈ ClN₃ O₆ S.requires C; 44.61 H, 4.49; N, 10.41. m.p. 244°-247° C.

EXAMPLE 18N-(3-Carboxypropyl)-N-(1,4-dihydro-6-chloro-7-methyl-2,3-dioxoquinoxalin-5-yl)methanesulphonamide##STR23##

(a)N-(6-Chloro-7-methyl-2,3-dimethoxyquinoxalin-5-yl)-N-(3-methoxycarbonylpropyl)methanesulphonamidewas prepared fromN-(6-chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)methanesulphonamide(Example 5, step (a)) (250 mg, 0.75 mmol) by the method of Example 3,step (g), substituting methyl4-bromobutyrate (273 mg, 1.57 mmol) formethylbromoacetate, and obtained as a white solid (199 mg, 61%).

¹ H NMR (300 MHz, CDCl₃): δ=1.85 (2H,m), 2.49 (2H,t, J6 Hz), 2.58(3H,s), 3.20 (3H,s), 3.64 (3H,s), 4.88 (2H,m), 4.26 (3H,s), 4.28 (3H,s),7.70 (1H,s). m/z (thermospray) 432 MH⁺.

(b) The title compound was prepared fromN-(6-chloro-7-methyl-2,3-dimethoxyquinoxalin-5-yl)-N-(3-methoxycarbonylpropyl)methanesulphonamide (242 mg,0.56 mmol) by the method of Example 1 step (i) and was obtained as abeige solid (171 mg, 78%).

Analysis %: Found, C,42.22; H,4.23; N,10.31. C₁₄ H₁₆ ClN₃ O₆ S.0.5 H₂ Orequires C,42.16; H,4.30; N,10.54. m.p. 285°-287° C.

EXAMPLE 19N-(2-Carboxyethyl)-N-(1,4-dihydro-6-chloro-7-methyl-2,3-dioxoquinoxalin-5-yl)methanesulphonamide##STR24##

(a)N-(6-chloro-7-methyl-2,3-dimethoxyquinoxalin-5-yl)-N-(3-hydroxypropyl)methanesulphonamidewas prepared fromN-(6-chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)methanesulphonamide(Example 5, step (a)) (1.0 g, 3.01 mmol) by the method of Example 3,step (g) substituting 3-bromo-1-propanol (0.84 g, 6.03 mmol) formethylbromoacetate and obtained as a white solid (1.05 g, 89%).

¹ H NMR (300 MHz, CDCl₃): 1.62-1.78 (2H,m), 2.58 (3H,s), 3.19 (3H,s),3.78-4.10 (4H,m), 4.15 (3H,s), 4.18 (3H,s), 7.72 (1H,s). m/z(thermospray) 390 MH⁺.

(b)N-(6-Chloro-7-methyl-2,3-dimethoxyquinoxalin-5-yl)-N-(3-hydroxypropyl)methanesulphonamide(0.94 g, 2.41 mmol) and pyridinium dichromate (2.42 g, 9.63 mmol) in DMF(24 ml) were stirred at room temperature for 18 hours. The reactionmixture was poured into water (25 ml) and extracted twice withdichloromethane. The combined dichloromethane extracts were extractedtwice with 10% potassium carbonate solution. The potassium carbonateextracts were acidified to pH1 with 2M HCl and extracted twice withdichloromethane. These combined dichloromethane extracts were dried(MgSO₄) and concentrated under reduced pressure to giveN-(2-carboxyethyl)-N-(6-chloro-7-methyl-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamidean off-white solid (0.49 g, 51%).

¹ H NMR (300 MHz, CDCl₃): 2.57 (3H,s), 2.69 (2H,m), 3.22 (3H,s), 4.09(2H, obs), 4,12 (3H,s), 4.16 (3H,s), 7.70 (1H,s). m/z (thermospray) 404MH⁺.

(c) The title compound was prepared from the product of step (b) (560mg, 1.39 mmol) by the method of Example 1, step (i), and was obtained asan off-white solid (400 mg, 77%).

¹ H NMR (300 MHz, DMSO-d₆): 2.31 (3H,s), 2.37-2.77 (2H, obscured m),3.19 (3H,s), 3.71-3.83 (1H,m), 3.89-4.00 (1H,m), 7.07 (1H,s), 11.62(1H,brs), 12.09 (1H,brs). m/z (thermospray) 393 MNH₄ ⁺.

EXAMPLE 20N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)-N-(methanesulphonylamino-2-oxo-ethyl)methanesulphonamide##STR25##

(a) DMF (8 mg, 0.11 mmol) was added dropwise to a suspension ofN-(carboxymethyl)-N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide(450 mg, 1.10 mmol, see Example 14, step (a)) and oxalyl chloride (209mg, 1.65 mmol) causing an evolution of gas. After stirring at roomtemperature for 30 minutes all the solid had dissolved and the gasevolution had ceased giving a solution of the acid chloride (solutionA).

Sodium hydride (53 mg, 2.19 mmol) was suspended in DMF at 0° C. undernitrogen. Methanesulphonamide (209 mg, 2.19 mmol) was added in twoportions to the sodium hydride and a gas evolution occurred (solutionB). The reaction mixture was stirred at 0° C. for 10 minutes. Solution Awas added via cannula to solution B forming a brown solution which wasstirred at room temperature for 18 hours. The reaction mixture wasconcentrated under reduced pressure and the brown residue dissolved indichloromethane. The dichloromethane solution was washed with 2Mhydrochloric acid, water and saturated brine and then dried (MgSO₄) andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with 95:5 dichloromethane:methanolto giveN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(methanesulphonylamino-2-oxo-ethyl)methanesulphonamide(174 mg, 33%).

¹ H NMR (300 MHz, CDCl₃) δ: 3.19 (3H,s), 3.23 (3H,s), 4.18 (3H,s), 4.30(3H,s), 4.51 (2H,q, J17 Hz), 8.01 (1H,s, obs). m/z (thermospray) 487MH⁺.

(b) The title compound was prepared from the product of step (a) (170mg, 0.35 mmol) by the method of Example 1, step (i), but purifying thesolid by flash chromatography on silica gel eluting with 9:1dichloromethane:methanol to give an off-white solid (82 mg, 51%).

¹ H NMR (300 MHz, DMSO-d₆): δ=2.78 (3H,s), 3.29 (3H,s), 3.63 (1H,d, J18Hz), 4.26 (1H,d, J18 Hz), 7.26 (1H,s), 13.30 (1H,br,s). m/z(thermospray) 476 MNH₄ ⁺.

EXAMPLE 21 N-(1,4-dihydro-6-chloro-7-methyl-2,3-dioxoquinoxalin-5-yl)-N-3-(2-naphthyl)-3-carboxypropyl!methanesulphonamide ##STR26##

(a) Sodium hydride (0.28 9, 11.7 mmol) was suspended in DMF (20 ml) at0° C. under nitrogen. 2-(Methoxycarbonylmethyl)naphthalene (J. Am. Chem.Soc., 1971, 93, 4919, 2.13 g, 10.6 mmol) dissolved in DMF (20 ml) wasadded dropwise to the suspension forming a deep yellow solution. Thereaction mixture was stirred at 0° C. for 1 hour.2-Bromo-1-(2'-tetrahydropyranylhydroxy)ethane (J. Med. Chem., 1975, 18,p992; 2.67 g, 12.8 mmol) dissolved in DMF (20 ml) was added dropwise tothe reaction mixture and stirred for 18 hours. The reaction mixture wasconcentrated under reduced pressure. The solid was dissolved indichloromethane and washed with water, saturated ammonium chloridesolution, water and saturated brine and then dried (MgSO₄) andconcentrated under reduced pressure. The resulting solid was purified byflash chromatography on silica gel eluting with 1:1dichloromethane:hexane to give 2-3-(2-naphthyl)-3-(methoxycarbonyl)propyloxy!tetrahydropyran as a paleyellow oil (2.00 g, 57%).

¹ H NMR (300 MHz CDCl₃): δ=1.45-1.61 (2H,m, obs), 1.62-1.78 (1H,m),1.78-1.92 (1H,m), 2.06-2.20 (1H,m), 2.42-2.59 (1H,m), 3.21-3.31 (1H,m),3.32-3.52 (2H,m), 3.63 (3H,s), 3.70-3.90 (2H,m), 4.93-4.01 (1H,m), 4.46(1H, brs), 4.52 (1H, brs), 7.20-7.50 (3H,m), 7.70-7.83 (4H,m). m/z(thermospray) 346 MNH₄ ⁺.

(b) The product of step (a) (2.0 g, 6.1 mmol) and carbon tetrabromide(2.83 g, 8.5 mmol) were dissolved in dichloromethane (30 ml) and cooledto 0° C. under nitrogen. Triphenylphosphine (4.48 g, 17.1 mmol) wasadded portionwise turning the reaction mixture deep yellow. Afterstirring at room temperature for 18 hours the reaction mixture wasconcentrated under reduced pressure. The oil was purified by flashchromatography on silica gel eluting with 1:1 dichloromethane:hexane togive 1-bromo-3-(methoxycarbonyl)-3-(2-naphthyl)propane as a white solid(0.56 g, 30%).

¹ H NMR (300 MHz, CDCl₃): δ=2.58-2.68 (1H,m), 2.60-2.76 (1H,m),3.18-3.26 (1H,m), 3.38-3.45 (1H,m), 3.66 (3H,s), 4.07 (1H,t, J8 Hz),7.39-7.52 (3H,m), 7.77 (1H,s), 7.82 (3H,m).

(c) N-(6-Chloro-7-methyl-2,3-dimethoxyquinoxalin-5-yl)-N-3-(2-naphthyl)-3-(methoxycarbonyl)propyl!methanesulphonamide wasprepared fromN-(6-chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)methanesulphonamide(Example 5, step (a)) (250 mg, 0.75 mmol) by the method of Example 3step (g), but substituting1-bromo-3-(methoxycarbonyl)-3-(2-naphthyl)propane (463 mg, 1.51 mmol)for methylbromoacetate, and obtained as a white foam (335 mg, 80%).

Analysis %: Found, C,57.39; H,5.02; N,7.43. C₂₇ H₂₈ ClN₃ O₆ S.1/2 H₂ Orequires C,57.19; H,5.15; N,7.41. m/z (thermospray) 558 MH⁺.

(d) The title compound was prepared from the product of step (c) by themethod of Example 1, step (i). The solid was purified by flashchromatography on silica gel eluting with 9:1 dichloromethane:methanolto give a pale pink solid (239 mg, 80%).

Analysis %: Found, C,52.44; H,4.47; N,7.57. C₂₄ H₂₂ ClN₃ O₆ S.H₂ O.1/4dichloromethane requires C,52.46, H,4.45; N,7.57. m.p. 215° C.(decomposes).

EXAMPLE 22

The binding affinity for the glycine site of the NMDA receptor of someof the compounds of the examples were determined in test (a) above, andthose found to have an IC₅₀ of less than 100nM included the compounds ofthe following examples: 1, 2, 3, 4, 5 the (-)-isomer!, 7, 10, 11 and 12.

We claim:
 1. A compound of formula I, ##STR27## wherein R¹ and R²independently represent Cl or C₁₋₆ alkyl;R³ represents XCO₂ R⁴, XCONHSO₂R⁵, YNHSO₂ R⁵ or XR⁶ ; R⁴ represents H or C₁₋₆ alkyl optionallysubstituted by aryl or heterocyclyl; R⁵ represents CF₃, heterocyclyl orC₁₋₆ alkyl optionally substituted by aryl or heterocyclyl R⁶ representsan acidic heterocycle; X represents a C₁₋₆ alkyl diradical optionallysubstituted by aryl or heterocyclyl; and Y represents a C₂₋₆ alkyldiradical optionally substituted by aryl or heterocyclyl; provided thatwhen R¹ and R² each represent Cl or C₁₋₄, then R³ does not representXCO₂ H, CH₂ CO₂ CH₃, CH₂ CH₂ NHSO₂ CF₃ or 5-tetrazolylmethyl; andpharmaceutically acceptable salts thereof.
 2. A compound as claimed inclaim 1, wherein R¹ represents Cl.
 3. A compound as claimed in claim 1,wherein R² represents methyl.
 4. A compound as claimed in claim 1wherein R³ represents CH₂ CO₂ H, CH(CH₃)CO₂ H, or (CH₂)₃ CO₂ H.
 5. Apharmaceutical composition comprising a compound of formula I, asdefined in claim 1, or a pharmaceutically acceptable salt thereof, inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier.
 6. An anxiolytic, anticonvulsant, analgesic or neuroprotectivemethod of treatment, which comprises administration of a compound offormula I, as defined in claim 1, or a pharmaceutically acceptable saltthereof, to a patient in need of such treatment.
 7. A process for theproduction of a compound of formula I, as defined in claim 1, or apharmaceutically acceptable salt thereof, which comprises removing theprotecting groups from a compound of formula II, ##STR28## wherein R¹⁻³are as defined in claim 1 and P¹ and P² are hydroxy protecting groups,and where desired or necessary converting the resulting compound into apharmaceutically acceptable salt or vice versa.
 8. A compound of formulaII, as defined in claim 7.